Ethyl 6-chloro-5-cyanonicotinate → Ethyl 5-cyano-6-isobutylnicotinate

HRID 1820975Notes

Reaction equation

Cl[C:2]1[C:12]([C:13]#[N:14])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.[Br-].[CH2:16]([Zn+])[CH:17]([CH3:19])[CH3:18]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.CN1CCCC1=O>[C:13]([C:12]1[C:2]([CH2:16][CH:17]([CH3:19])[CH3:18])=[N:3][CH:4]=[C:5]([CH:11]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:14]

Participants

Conditions

Temperature: 65 °C

Procedure

To a solution of 145 mg (0.69 mmol) of ethyl 6-chloro-5-cyanonicotinate (from Step B), 1.65 mL (0.83 mmol) of isobutylzinc bromide (0.5 M in THF), and 100 mL of 1-methyl-2-pyrrolidinone was added 18 mg (0.03 mmol) bis(tri-tert-butylphosphine)palladium(0). After stirring at 65° C. overnight, the reaction mixture was cooled to rt and filtered through a cake of Celite. The filtrate was concentrated. Chromatography on a Biotage 40S cartridge using 1:19 v/v EtOAc/hexanes as the eluant gave 75 mg of the title compound: 1H NMR (500 MHz, CDCl3) δ 0.99 (d, J=6.7, 6H), 1.43 (t, J=7.1, 3H), 2.27 (m, 1H), 2.99 (d, J=7.3, 2H), 4.45 (q, J=7.1, 2H), 8.50 (d, J=2.1, 1H), 9.28 (d, J=2.3, 1H).

Workup

temperaturethe reaction mixture was cooled to rt
filtrationfiltered through a cake of Celite
concentrationThe filtrate was concentrated

Sources & evidence

ORD record: ord-a7c63d1658964633b14e63056146747a
Source dataset: uspto-grants-2009_10
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07605171B2

Reaction notes

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